Brevilin A induces ROS-dependent apoptosis and suppresses STAT3 activation by direct binding in human lung cancer cells

• Published in: Journal of Cancer 2020-01, Vol.11 (13), p.3725-3735
• Main Authors: Khan, Muhammad, Maryam, Amara, Saleem, Muhammad Zubair, Shakir, Hafiz Abdullah, Qazi, Javed Iqbal, Li, Yongming, Ma, Tonghui
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Cancer therapies; Cytotoxicity; Drug development; Drug resistance; Kinases; Lung cancer; Medical prognosis; Proteins; Research Paper
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.40983

Sesquiterpene lactones have been shown to be promising leads for anticancer drug development. Brevilin A (BLN-A), a sesquiterpene lactone compound of has been shown to exhibit anticancer effects against various cancer cells. However, the anticancer mechanism and cellular targets of BLN-A remain elusive. Here in this study, BLN-A inhibits proliferation and induces cell morphological changes in A549 and NCI-H1650 non-small cell lung cancer cells in a dose-dependent manner. Moreover, BLN-A increased ROS generation and bax/bcl-2 ratio while decreased intracellular glutathione (GSH), and mitochondrial membrane potential which resulted in induction of apoptosis as evident by annexin-V/FITC staining, caspase-3 activation and PARP cleavage. Supplementation of cells with NAC (ROS Scavenger) effectively protected the cells from BLN-A-induced apoptosis. Finally, BLN-A inhibited constitutive as well as IL-6- and EGF-induced STAT3 activation at Tyr705. Using molecular docking and SPR analyses, we found that BLN-A directly binds with STAT3 and thereby inhibits its activation. Knocking down of STAT3 by stable transfection with shRNA suppressed growth and augmented cytotoxicity of BLN-A, indicating the key role of STAT3 in BLN-A-mediated apoptosis. Cumulative findings suggest that BLN-A is a promising lead structure for developing it into a potent STAT3 inhibitor and therapeutic agent against NSCLC as well.